New Research on Brain Energy in

Mood and Psychotic DisordersBruce M. Cohen, M.D., Ph.D.

Director, Shervert Frazier Research Institute, McLean Hospital

President and Psychiatrist in Chief Emeritus, McLean Hospital

Robertson-Steele Professor of Psychiatry, Harvard Medical School

NAMI-MA October 30, 2010

Relevant Financial Relationships:

None

Relevant Personal Relationships:

Many

Suzann Babb, M.S. Jin Kim, B.A.Tom Berry, B.A. Nick Lange, Sc.D.Brian Brennan, M.D. Eve Lewandowski. Ph.D. Anne Carpenter, Ph.D. David Logan, Ph.D.Anne Cataldo, Ph.D. Jeanne Lothrop, B.S.Bruce M. Cohen, M.D., Ph.D. Julie McCarthy, B.A.Diane Damez-Werno, B.A. Donna McPhie, Ph.D.Joe DePaola, B.A. Emily Mensale, B.A. Sarah Elmiligy, B.A. Beth Murphy, M.D., Ph.D.Laura Flynn, B.A. Dost Öngür, M.D., Ph.D. Brent Forester, M.D. Caitlin Ravichandran, Ph.D.Jennifer Gelda, B.A. Laura Sargent, B.A.Linda Hassinger, M.S. Jordan Smoller, M.D., Sc.D.Hannah Irving, B.A. Nancy Ye, Ph.D.

List of Investigators Working on Project

A Caveat:

Bipolar disorders and other psychiatric disorders are not homogeneous or unitary

by cause or pathophysiology.

They are likely the consequence of the

interaction of numerous factors, both inherited and environmental, which differ

from person to person.

Problems in energy production may be one factor contributing

to the risk of developing bipolar

or other brain disorders

Energy production and brain disorders

Background:

Blood Flow and Metabolism of the

Human Brain in Health and Disease

Seymour S. Kety, M.D.

“The blood flow of the brain represents about

one-sixth of the cardiac output and its oxygen consumption nearly one quarter of that of the

entire body.”Trans Stud Coll Physicians Phila. 1950 Dec;18:103-8.

Seymour S. Kety, M.D.

Energy use of the brain changes little,

even in illness, except under extreme circumstances, such as

coma.

The brain maintains energy production within a narrow

margin.

The brain uses ten times more energy per

unit weight than the rest of the body

Even subtle abnormalities of energy metabolism can affect

brain function

Energy abnormalities have been observed

in many disorders of the brain

Why Is the Brain So Energy Dependent?

The Brain is a High-Precision

Electro-Chemical OrganThe brain must not only generate, but must quite

accurately control, numerous electrical and

chemical signals.

Each of these tasks is highly energy expensive, and the

energy must be made close to where it is used.

Pellerin and Magistretti, Science 2004

Raichle & Mintun, 2006

Nearly 99% of the energy production of the brain is used to support intrinsic (resting) activity. It is energy expensive just to

support the basic background state and

maintenance work of the brain.

Where Does the Brain Get Its Energy?

Most of the energy produced to support the work of the brain comes

from oxidative phosphorylation, the complete ‘burning’

(oxidation) of glucose (sugar) to carbon dioxide

and water.

Oxidative phosphorylation occurs in, and only in, subcellular organelles called mitochondria.

Energy Production and Bipolar Disorders

A variety of early studies, including:

GeneticIn vivo brain imagingPost mortem gene expressionPeripheral cell gene expressionCSF metabolite studies

All suggest abnormalities of energy metabolism in patients

with bipolar disorder

We looked directly at mitochondria

of patients with bipolar disorders.

We studied both brain and peripheral cells from public

tissue banks.

Mitochondrial Distribution in Brain Cells

(Post Mortem-Cytochrome C Staining)

Magnification 1,000X

CONTROL BIPOLAR DISEASE

BD Brains Have More Smaller Mitochondria

Than Control Brains (p<0.03)BD

Control

Area in Square Microns

Nu

mb

er

of M

itoch

ond

ria

Mitochondrial Shape Abnormalities in

Post Mortem Brain TissueCONTROL BIPOLAR DISORDER

EM Magnification 15,000X

Can We See Abnormalities in Peripheral Cells?

Is There an Abnormality of Mitochondrial Distribution in Peripheral Cells, as Observed

in Brain, in BD?

Mitochondria Look Abnormal in Fibroblasts

from Patients with Bipolar Disorder

Mitochondria from fibroblasts in patients with bipolar disorder

show an altered morphology consisting of short, thickened

profiles that are arranged in a predominantly perinuclear

location compared to age-matched controls.

Mitochondrial Network in Control

and BD Lymphocytes

Light Microscopy Magnification 1,000X

Quantification of Mitochondrial

Distribution in Fibroblasts

Quantification of Changes in Mitochondrial Distribution

BD vs. Control, p<0.0008

Are there more or fewer mitochondria in BD?

No Difference in Total Mitochondrial Area Between

Bipolar Disorder and Control Fibroblasts

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

Control BD

Square Pixels

Is the Difference in Distribution of Mitochondria

in BD a Drug Effect?(There was a wide assortment of drugs

taken by the subjects. Lithium was used by only half,

and its use was not correlated with the mitochondrial

abnormalities observed.)

Lithium Does Not Make Healthy Subject’s Cells Look Sick or BD

Cells Look HealthyNo Treatment 1mM Li2+

Control

BD

Are There Abnormalities of Mitochondrial Shape in Peripheral Cells,

as Observed in Brain, in BD?

Spherical and Cup Shaped Mitochondria

in BD Fibroblasts

BD

Magnification 1,000X

EM Magnification 10,000X

Quantification of Ring Shaped Mitochondria

in Control and BD Fibroblasts

• Ultrastructural images from thirty fibroblasts were obtained at random (magnification 10,000X by electron microscopy) from each of 4 healthy controls and 4 BD cell lines (in total, 120 controls fibroblasts and 120 BD fibroblasts).

• We found that the number of ring structures was increased in cells from the BD patients compared to controls (Controls<1, BD>1, per cell, p<0.01).

Is There a Functional Abnormality

of Mitochondria in Peripheral Cells in Bipolar Disorder?

Mitochondrial Membrane Potential Staining

(JC1) in Control and BD Fibroblasts

CONTROL BIPOLAR DISEASE

Red = Healthy Mitochondria

Green = Compromised Mitochondria with lower membrane potential

Are These Abnormalities Specific to BD?

Schizophrenic Patient’s Fibroblasts May Exhibit Distinct

Mitochondrial Abnormalities

Control Bipolar Disorder Schizophrenia

Magnification 630X

While consistent and from multiple sources, all of the evidence for abnormalities of

energy production or mitochondrial shape and

location in bipolar or related disorders

is subtle, preliminary and needs

confirmation

HOWEVER:

Future Directions: Much More To Do

By computerized analyses, we are determining

many features of the shape and distribution

of the mitochondrial network in our samples.

With electron microscopy, we have begun to look

at individual mitochondria in our samples.

We are studying mitochondrial function at McLean and in

collaboration with local colleagues.

Future Directions: Genetics

The risk of psychiatric illnesses is

highly determined by genetic factors.

Given our findings, might some of the

genes associated with bipolar disorders

and schizophrenias be genes formitochondrial form and function?

Many diseases are associated with abnormal levels or activities of

the proteins which perform cell

functions.

We have begun to look directly at proteins

known to be involved in determining

mitochondrial location, shape and activity.

Future Directions: Proteins

MITOCHONDRIAL MORPHOLOGICAL ABNORMALITIES

DYSREGULATION OF FUSION AND FISSION PROTEINS, WHICH

CONTROL MITOCHONDRIAL SHAPE, e.g. DRP1, ORA1

DYSREGULATION OF MOTOR PROTEINS, WHICH MOVE

MITOCHONDRIA IN THE CELL,e.g .MIRO, MISATO, MYOSIN V

DYSREGULATION OF CYTOSKELETAL PROTEINS,

TO WHICH MITOCHONDRIA ATTACH,

e.g. ACTIN, TUBULIN

There are no Large Scale Changes in the Actin Cytoskeleton in BD

Green = Mitochondria Red = Actin Blue = Nuclei

No Overall Changes are Seen in the Tubulin Cytoskeleton in BD

Control

BD

Red/Orange = mitochondria Green = Tubulin

Clinical trials: We are testing agents believed to

increase mitochondrial function

Brian Brennan et al -Acetyl-L-carnitine and alpha lipoic

acid for bipolar depression

Brent Forrester et al -Coenzyme Q10 for geriatric bipolar

depression

Can mitochondria be repaired or replaced?

Some Developing Technologies for Neurorepair

Gene Alteration

Nanomedicine

Organelle Replacement / Repair

Cell Replacement / Repair

Biofeedback and Cognitive Training

Healthy mitochondria can be isolated

from blood cells and might beused to replace dysfunctional mitochondria in damaged cells

Mitochondrial Transplantation

The Meaning of Our Results

Abnormalities of mitochondrial form, distribution and function may be important factors in determining risk for mood and psychotic disorders.

If so, we should be able to identify the causes of those mitochondrial abnormalities and use that knowledge to design better treatments and preventive measures for psychiatric illnesses.

To all my colleagues who worked, and keep working,

so hard and well on these projects.(Anne would be pleased.)

THANKS

To NAMI, for all it’s work to improve lives,

advance knowledge and improve our society.

Good science and good lives are collaborations.

Art and Science: The Paintings

of Lynda Cutrell